Stress responses are vital to an organism's survival and as such these responses are tightly regulated by a host of signaling molecules within the central and peripheral nervous system. There is a large body of evidence to suggest that severe and chronic stress lead to dysregulation of the normal stress-related electrochemical signaling in the nervous system, which in turn predispose the individual to disease. There is a broad spectrum of stress related diseases ranging from pathologies such as irritable bowel syndrome to cardiac disease to depression. Using animal models, recent studies have posited a role for the dynorphin- kappa opioid receptor (KOR) neuropeptide system in mediating the aversive and pro-depressive components of repeated stress. Stress-induced dynorphin release and subsequent KOR activation occurs in various forebrain limbic brain regions, one of which is the serotonergic dorsal raphe nucleus (DRN). There is a well-established literature implicating the DRN-serotonin projection system in mediating stress responses and stress-related pathology. The DRN receives numerous excitatory and inhibitory inputs and is tonically controlled by serotonergic autoinhibition;all of these inputs control DRN net excitability and ultimately serotonin release into the forebrain. Despite evidence that KORs are present in the DRN, the functional role of KORs in modulating excitability of this region is poorly understood. Using a combination of electrophysiology and fast scan cyclic voltammetry in an acute brain slice preparation, the first aim of this proposal assesses the neuromodulatory role of KORs on excitatory and inhibitory inputs in DRN. Very little is known about how the functioning of the kappa opioid or serotonin system is altered when an organism is exposed to repeated stress, let alone how the interaction between these two systems is altered. Thus, using an established behavioral animal model of repeated stress, the second aim of this application will examine stress-induced cellular alterations in KOR neuromodulation in DRN. In order to advance therapies for stress related diseases it is critical to understand the molecular, cellular and systems level changes that occur in the brain following repeated stress. This line of research further elucidates the cellular mechanisms underlying maladaptive stress responses that make individuals vulnerable to disease.